DESCRIPTION (adapted from investigators abstract) The global working hypothesis is that oxidative stress induced by cerebral ischemia and reperfusion is involved in neuronal cell death through both the necrosis and apoptosis pathways. The hypothesis will be tested using transgenic mice overexpressing human CuZn-SOD (SOD-1) and knockout mutants that contain no (homozygous) or one-half of (heterozygous) SOD-1 activity. Since mitochondria are known to be the site of oxygen radical production, it is also hypothesized that increased oxidative stress to mitochondria by either mitochondrial toxins or by the null mutation of mitochondrial manganese SOD (sod-2) in knockout mutants will increase neuronal susceptibility to necrosis and/or apoptosis following cerebral ischemia and reperfusion. In order to dissect out the rule of nitric oxide in ischemic brain injury associated with superoxide radicals, various combinations of SOD-1 transgenic mice and neuronal NOS knockout mutants will be employed.